Synaptic dysfunction and neuronal death are responsible for cognitive and behavioral deficits in Alzheimer's disease (AD). It is well known that such neurological abnormalities are preceded by long-term exposure of amyloid β-peptide (Aβ) and/or hyperphosphorylated tau prior. In addition to the neurological deficit, astrocytes as a major glial cell type in the brain, significantly participate in the neuropathogenic mechanisms underlying synaptic modulation. Although astrocytes play a significant key role in modulating synaptic transmission, little is known on whether astrocyte dysfunction caused by such long-term Aβ exposure affects synapse formation and function. Here, we show that synapse formation and synaptic transmission are attenuated in hippocampal-naïve neurons co-cultured with astrocytes that have previously experienced chronic Aβ exposure. In this abnormal astrocytic condition, hippocampal neurons exhibit decrements of evoked excitatory post-synaptic currents (EPSCs) and miniature EPSC frequency. Furthermore, size of readily releasable synaptic pools and number of excitatory synapses were also significantly decreased. Contrary to these negative effects, release probability at individual synapses was significantly increased in the same astrocytic condition. Taken together, our data indicate that lower synaptic transmission caused by astrocytes previously, and chronically, exposed to Aβ1-40 is attributable to a small number of synapses with higher release probability.

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Highlights We exposed astrocytes to Aβ 25-35 and then co-cultured them with primary hippocampal neurons. The Aβ 25-35 -exposed astrocytes lowered excitatory postsynaptic release and the size of the readily releasable synaptic pool. The number of excitatory synapses was reduced by direct contact between Aβ 25-35 -exposed astrocytes and hippocampal neurons. The dendritic branching was decreased by direct contact between Aβ 25-35 -exposed astrocytes and hippocampal neurons. The number of excitatory synapses and dendrite branches were conserved by putting distance from Aβ 25-35 -exposed astrocytes.

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Valproic acid (VPA) is widely prescribed to treat epilepsy. Maternal VPA use is, however, clinically restricted because of the severe risk that VPA may cause neurodevelopmental disorders in offspring, such as autism spectrum disorder. Understanding the negative action of VPA may help to prevent VPA-induced neurodevelopmental disorders. Astrocytes play a vital role in neurodevelopment and synapse function; however, the impact of VPA on astrocyte involvement in neurodevelopment and synapse function has not been examined. In this study, we examined whether exposure of cultured astrocytes to VPA alters neuronal morphology and synapse function of co-cultured neurons. We show that synaptic transmission by inhibitory neurons was small because VPA-exposed astrocytes reduced the number of inhibitory synapses. However, synaptic transmission by excitatory neurons and the number of excitatory synapses were normal with VPA-exposed astrocytes. VPA-exposed astrocytes did not affect the morphology of inhibitory neurons. These data indicate that VPA-exposed astrocytes impair synaptogenesis specifically of inhibitory neurons. Our results indicate that maternal use of VPA would affect not only neurons but also astrocytes and would result in perturbed astrocyte-mediated neurodevelopment.